Risk factors of dermatophytosis among Korean adults

Dermatophytosis includes all fungal infections caused by dermatophytes in humans. Some risk factors for the development of subtypes of dermatophytosis have been studied; however, large-scale epidemiologic studies on risk factors for total dermatophytosis are scarce. We investigated the risk factors of dermatophytosis using a nationwide study. Total 4,532,655 subjects with dermatophytosis aged between 20 and 40 years were examined using data from the Korean National Health Insurance Service from 2009 to 2018. Women showed a lower risk of development of dermatophytosis compared to men [hazard ratio (HR) 0.848; 95% confidence interval (CI) 0.843–0.853]. Subjects with elevated waist circumference (HR 1.057; 95% CI 1.048–1.065), heavy drinking (HR 1.053; 95% CI 1044–1.061), engaging in mild-to-heavy exercise (HR 1.071; 95% CI 1.064–1.077) had a higher risk of dermatophytosis. In addition, subjects with body mass index (BMI) of more than 30 kg/m2 exhibited a higher risk of dermatophytosis (HR 1.36; 95% CI 1.342–1.378) compared to those with BMIs in the range of 18.5–23 kg/m2. In this study, the risk of developing dermatophytosis significantly increased in individuals with elevated waist circumference or high BMI. Lifestyle modifications, including weight management, are suggested to be important in preventing dermatophytosis.

Clinical, laboratory, and anthropometric measurements. Data on sex, age, household income, alcohol consumption, smoking status, physical activity, comorbidities, waist circumference, body mass index (BMI), and lipid profiles were collected for the study. Demographic data of sex, age, and household income which was dichotomized at lower 20% (≤ 20% vs. > 20%)-were obtained from the results of the regular medical check-up programs of the KNHIS. Detailed histories about alcohol consumption, smoking status, and physical activity, including the amount and frequency, were obtained via a questionnaire given during the KNHIS health check-up programs. In this study, smoking status was classified as non-smoker, ex-smoker, or current smoker, and alcohol consumption was classified as abstinence (no alcoholic drinks consumed within the last year), moderate drinking (< 30 g of pure alcohol per day), or heavy drinking (≥ 30 g of pure alcohol per day). Physical activity was classified as none or moderate-to-severe. Moderate-to-severe physical activity was defined as 5 days or more of moderate-intensity exercise per week or 3 days or more of vigorous-intensity exercise per week. A history of comorbidities, including hypertension, dyslipidemia, and diabetes mellitus, was identified based on the combination of ICD-10 clinic and pharmacy codes and a list of prescribed medicines. Venous blood samples  Statistical analysis and ethics statement. Baseline demographic characteristics of the study population are described using numbers and percentages or mean ± standard deviation values. An independent t-test for continuous variables and a chi-squared test for categorical variables, respectively, were used to analyze the differences in characteristics between the dermatophytosis group and non-dermatophytosis group. To evaluate the risk of development of dermatophytosis, Cox proportional hazards regression analyses were performed; then, multivariate Cox proportional hazard regression analyses were performed with variables showing a P-value of less than 0.05 in the univariate analysis used to determine the association between suspected risk factors and the prospective development of dermatophytosis. Lastly, cumulative incidence rates of dermatophytosis for the follow-up period were analyzed using the Kaplan-Meier method, and log-rank tests were performed to analyze the differences in the incidence of dermatophytosis between the BMI groups adjusted for other confounding variables, such as sex, age, alcohol consumption, smoking status, physical activity, household income, diabetes mellitus, hypertension, and dyslipidemia. All the statistical analyses were performed using the SAS software program (version 9.4; SAS Institute, Cary, NC, USA), and P-values less than 0.05 were considered to be statistically significant.

Results
Characteristics of the study population. During the study period, 861,840 dermatophytosis cases occurred among the 4,532,665 study subjects. Table 1 shows the characteristics of the study population, comparing the dermatophytosis and the non-dermatophytosis groups. Both groups showed statistically significant differences (P < 0.001) in all of the variables collected for this study. The dermatophytosis group tended to be older (30.86 vs. 30.41 years; P < 0.001) and had greater proportions of men (62.59% vs. 55.56%; P < 0.001), heavy drinkers (9.34% vs. 8.37%; P < 0.001), current smokers (36.44% vs. 34.75%; P < 0.001), ex-smokers (11.49% vs. 9.53%; P < 0.001), and those engaging in moderate-to-intense physical activity (13.46% vs. 11.95%; P < 0.001). The dermatophytosis group also had a smaller portion of those with low income compared to the non-dermatophytosis group (14.72% vs. 17.09%; P < 0.001) and exhibited a greater waist circumference (14.21% vs. 11.08%; P < 0.001) and higher prevalence rates of diabetes (1.99% vs. 1.74%; P < 0.001), dyslipidemia (7.08% vs. 6.33%; P < 0.001), and hypertension (7.59% vs. 6.83%; P < 0.001) compared to the non-dermatophytosis group. Cumulative impact of BMI status on dermatophytosis incidence. The results of Kaplan-Meier analysis for the cumulative incidence rates of dermatophytosis based on the BMI status adjusted for sex, age, alcohol consumption, smoking status, physical activity, household income, diabetes mellitus, hypertension, and dyslipidemia are shown in Fig. 2. The cumulative incidence rates of dermatophytosis increased linearly and showed a steeper increase in higher BMI groups (P < 0.0001, log-rank test; Fig. 2.).

Discussion
In this large-scale nationwide study of the Korean population, the data of 4,532,665 subjects aged between 20 and 40 years were analyzed to determine the risk factors associated with the development of dermatophytosis in Korea. Notably, women were less likely to be infected by dermatophytes than men, while those who were older and those with higher incomes; higher blood pressure values; higher low-density lipoprotein cholesterol levels; lower high-density lipoprotein cholesterol levels; and more comorbidities, such as diabetes, dyslipidemia, and hypertension, were determined to be more susceptible to dermatophytosis. Also, drinking more alcohol, performing exercise more frequently, having a history of smoking, and having a greater waist circumference also increased the risk of developing a dermatophyte infection, even after adjusting the confounding factors. It has been widely reported that dermatophytosis is associated with male sex; a systemic or local immunocompromised status, such as diabetes mellitus; and long-term use of topical steroids 9,10 . Previous known risk factors of tinea pedis and onychomycosis, the most common types of tinea, accounting for 33% to 40% of all dermatophytosis, includes advanced age; male sex; nail trauma; peripheral vascular insufficiency; and immunosuppression status, such as diabetes mellitus and human immunodeficiency virus infection 9,11 . Warm and Table 1. Characteristics of the study population. Values are expressed as mean ± standard deviation or n (%) by independent t-test (continuous variables) or chi-squared test (categorical variables). HDL high-density lipoprotein, LDL low-density lipoprotein. a Low income is defined as a household income of 20% or less of the median. b Elevated waist circumference is defined as a waist circumference of more than 90 cm in men or more than 85 cm in women. www.nature.com/scientificreports/ humid foot conditions secondary to wearing tight shoes; performing specific sporting activities, such as swimming; smoking; and obesity were also reported to increase the risk of tinea pedis and onychomycosis [11][12][13] . On the other hand, tinea capitis mainly occurs in children between the ages of three and 14 fours, and known risk factors include male sex, low socioeconomic status, overcrowding, and keeping pets at home 14,15 . Meanwhile, tinea capitis in the adult population is highly associated with comorbidities, such as rheumatoid arthritis, human immunodeficiency virus infection, diabetes mellitus, leukemia, and kidney failure 15 . In this study, male sex, advanced age, obesity, alcohol consumption, and moderate to heavy exercise were shown as risk factors for the development of dermatophytosis. Among these risk factors, sex was the most influential variable. Tinea cruris is the most known sex-influenced dermatophytosis, found to be three times more common in men than in women 14 . In addition, men also have a higher risk of developing tinea pedis than women, which also may be due to their more common exposure to moist environments due to wearing of occlusive footwear and more frequent physical exercise 14 . These aforementioned lifestyle characteristics more commonly associated with male sex are thought to be responsible for the high prevalence of dermatophytosis in men; however, it is not yet understood whether male sex itself increases the susceptibility to infection 10,14 .
In our study, advanced age was shown to be the risk factor for developing dermatophytosis. Yoon et al. 4 reported that the prevalence of dermatophytosis in Korea continuously increases with age, and the highest prevalence is among those aged between 60 and 69 years old. Among the types of dermatophytosis, onychomycosis, which is the most common superficial fungal infection, has been confirmed to increase with age 16 . Eleweski and Charif 17 reported that approximately 40% of elderly patients have onychomycosis. The presumed cause for this high prevalence was to be that older individuals find it more difficult to exercise and care for feet and nails, increasing their susceptibility to colonization by infectious organisms 16,17 . Predisposing conditions, such as diabetes and compromised peripheral circulation, were also thought to be contributing causes 16,17 . These contributing factors, however, are thought to increase the prevalence of infection by all kinds of dermatophytes.
Obesity, expressed through the BMI index and waist circumference, was also found to be a significant contributing factor to the development of dermatophytosis. Onychomycosis has been relatively well studied regarding its relationship with obesity [18][19][20] . In a study of more than 1000 patients randomly screened to examine their feet, obesity was found to be one of the most prevalent predisposing factors among patients with fungal nail disease 18 . Onychomycosis was significantly increased in patients with obesity (odds ratio 2.13; 95% CI 1.45-3.13) in a study of 1245 diabetic Taiwanese patients 19 . In addition, topical antifungal treatment was shown to be less effective in patients who were overweight or obese 20 . Complete cure rates were 15.9% in obese patients and 22.0% in patients with healthy BMIs after 52 weeks of applying topical efinaconzole 20 . Several factors have been proposed to explain the potential mechanism behind the results. Firstly, obesity might make the skin more hospitable to fungal growth. Humid and warm conditions are important for fungal growth and survival. Thick layers of subcutaneous fat with deep skin folds may cause profuse sweating, and the trapped moisture and warmth may provide an optimal environment for the colonization of the dermatophytes 21,22 . Secondly, increased adipose tissue itself may further contribute to the increased risk for infection [23][24][25] . It has been recently recognized that adipose tissue participates actively in immunity through producing a variety of cytokines, such as leptin and adiponectin 24,25 . Leptin is a pro-inflammatory cytokine that activates polymorphonuclear neutrophils and T lymphocytes and regulates the activation of monocytes and macrophages 24,25 . However, obese patients often show leptin resistance, making them more vulnerable to infection 23 . Also, obese patients are more likely to have comorbidities, such as diabetes mellitus, which further contributes to the development of dermatophytosis 21,23 .
Lastly, engaging in routine exercise was also associated with an increased incidence of dermatophytosis. This is thought to be due to the wet environment caused by sweating from physical activities. However, as obesity is critical for the development of dermatophytosis and exercise is essential for maintaining a healthy weight, exercise should not be discouraged to manage the risk of developing dermatophytosis itself; instead, self-hygiene activities to keep the body clean and dry following each exercise session should be highlighted to reduce the risk of dermatophytosis after exercise.
This study also had some limitations. Firstly, dermatophytosis and comorbidities, such as hypertension, diabetes mellitus, and dyslipidemia, were identified using ICD-10 codes from claims databases. However, a validation study of the diagnostic codes of the KNHIS claims database revealed that only approximately 70% of the diagnosis codes coincided with those from medical records 26 . Secondly, dermatophytosis has some different clinical characteristics depending on the anatomic sites of infection, but this study did not distinguish these subtypes and was conducted while considering all subtypes of dermatophytosis as a whole. However, it is still meaningful to find out the risk factors for dermatophytosis as a whole without losing the significance since the fungi invading the skin share similar common characteristics. In contrast, the strengths of this study are its large sample size and nationally representative study population. Moreover, the national database contained information on sociodemographic characteristics, such as smoking status, alcohol consumption, physical activity, household income, and BMI, which were all found to be significant variables in the risk of developing a dermatophyte infection.
Taken together, our results demonstrated a significant positive association between the incidence of dermatophytosis and increasing BMI. In addition to male sex and increasing age, an elevated waist circumference, drinking, and exercise all contributed to the development of dermatophytosis. It is emphasized that lifestyle corrections directed at managing weight, drinking less alcohol, and keeping the body clean and dry after exercise might contribute to the prevention of dermatophytosis.

Data availability
The data that support the findings of this study are available from the Health Insurance Review & Assessment Service (HIRA). Restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available due to personal information protection. Data are available at https:// opend ata. hira. or. kr/ with the permission of the HIRA.